Amphotericin B Encapsulated in Micelles Based on Poly(ethylene oxide)-block-poly(-amino acid) Derivatives Exerts Reduced in Vitro Hemolysis but Maintains Potent in

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• 作者：Monica L. Adams ; David R. Andes ; and Glen S. Kwon
• 刊名：Biomacromolecules
• 出版年：2003
• 出版时间：May 2003
• 年：2003
• 卷：4
• 期：3
• 页码：750 - 757
• 全文大小：118K
• 年卷期：v.4,no.3(May 2003)
• ISSN：1526-4602

文摘

The core-forming blocks of amphiphilic diblock copolymers based on methoxypoly(ethylene oxide)-block-poly(L-aspartate), PEO-b-p(L-Asp), were derivatized to incorporate stearate side chains. The effects of stearateesterification were assessed in terms of micelle stability and amphotericin B (AmB) encapsulation/release.The level of stearate esterification modulates the relative self-aggregation state of encapsulated AmB asevidenced by absorption spectroscopy. When AmB is physically loaded into polymeric micelles, the onsetof hemolytic activity toward bovine erythrocytes is delayed relative to that of the free drug. Furthermore,the extent of esterification (0, 46, or 91%) appears to have profound influence on the time-dependent hemolyticprofile of AmB toward bovine erythrocytes. Particularly in the case of highly substituted stearate estermicelles, incomplete and gradual build-up of hemolysis was observed over a period of 24 h. On the basisof the corresponding absorption spectra, we speculate that encapsulated AmB may interact strongly withstearate side chains, resulting in sustained release. In a neutropenic murine model of disseminated candidiasis,kidney colony-forming unit determination revealed dose-dependent efficacy for the polymeric micelle/AmBformulation, which was not significantly different from that of Fungizone at doses of 0.2, 0.3, and 0.6mg/kg (p = 0.7). Thus, AmB administered via a polymeric micelle formulation retained potent in vivoactivity.